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  • Difference f c nd s??Paroxetine== most A/Es…Fluvoxamine- nausea
  • antidepressants, which affect other monoamine neurotransmitters as well.
  • 5-hydroxytryptamine 5-HT.. 14 distinct downstream serotonin receptors (5-HT receptors).
  • Hypo nd midbrain e beshi
  • They act upon two neurotransmitters in the brain that are known to play an important part in mood, namely, serotonin and norepinephrine. This can be contrasted with the more widely-used selective serotonin reuptake inhibitors (SSRIs), which act only on serotonin.
  • Sertraline- 200max. Though >100mg no help. TCA- 75-100
  • Life threatning
  • CP450 inhibitors
  • When SS occurs?
  • Receptor rebound…..Onset within 5 dayz f stopping treatment. Or during tapper or in missed dose….treatment??– mild- no rx others- reintroduce or another f same class with longer half life..
  • SIADH… 5Ht regulation f ADH…So SSRI n SNRI more…..
  • citalopram
  • Vascular injury------ platelet---- release f 5HT---- Vaso constricton. 5HT s a weak platelet aggregator. SSRI inhibit the 5HT transporter responsible fr uptake f 5HT n platelet
  • Fluoxetine--- insulin req reduced, HBA1c improved, wt loss…. Limited data n venla
  • Citalopram- QT prolong…. Dnt go fr SNRI. Tolerance…bp
  • 10 mg start n hepatic
  • – active monitoring, individual guided self-help, CBT or exercise are preferred in these cases
  • ssnri

    2. 2. Depression <ul><li>3 rd largest cause of burden of disease </li></ul><ul><li>GLOBAL BURDEN OF DISEASE STUDY 1995 SHOWS UNIPOLAR DEPRESSION 2nd to Coronary disease by 2020 ; 1 st by 2030 </li></ul>
    3. 3. Prevalence in Bangladesh <ul><li>WHO + NIMH---- ‘03-‘05 </li></ul><ul><li>Psychiatric disorder ---- >18 yrs --- 16.05%. </li></ul><ul><li>MDD--- 4.6% </li></ul><ul><li>GAD--- 2.9% </li></ul><ul><li>Somatoform D--- 1.4% </li></ul><ul><li>Panic--- 1.3% </li></ul><ul><li>Agorophobia—0.9% </li></ul><ul><li>OCD--- 0.5% </li></ul><ul><li>Simple Phobia--- 0.3% </li></ul>
    4. 4. Antidepressants <ul><ul><li>Tricyclic antidepressants (TCA) </li></ul></ul><ul><ul><li>Monoamine oxidase inhibitors (MAOI) </li></ul></ul><ul><ul><li>Selective Serotonin Re-uptake Inhibitors (SSRI) </li></ul></ul><ul><ul><li>Other and atypical antidepressant </li></ul></ul><ul><ul><ul><li>Serotonin-2 Antagonists/Reuptake Inhibitors (SARI) </li></ul></ul></ul><ul><ul><ul><li>Serotonin and Noradrenaline Reuptake Inhibitors (SNRI) </li></ul></ul></ul><ul><ul><ul><li>Noradrenaline and Dopamine Reuptake Inhibitors (NDRI) </li></ul></ul></ul><ul><ul><ul><li>Noradrenaline Reuptake Inhibitors (NaRI) </li></ul></ul></ul><ul><ul><ul><li>Noradrenergic/Specific Serotonergic Antidepressants (NaSSA) </li></ul></ul></ul>
    5. 5. <ul><li>HOW DOES THE MOST ANTIDEPRESSANTS WORK?? </li></ul>
    6. 6. Neurotransmitter Receptor Hypothesis of Antidepressant Action Decreased state due to up-regulation of receptors Stahl S M, Essential Psychopharmacology (2000)
    7. 7. Neurotransmitter Receptor Hypothesis of Antidepressant Action Antidepressant blocks the reuptake pump, causing more NT to be in the synapse Increase in NT causes receptors to down-regulate Stahl S M, Essential Psychopharmacology (2000)
    8. 8. SSRI’s <ul><li>Citalopram </li></ul><ul><li>Escitalopram </li></ul><ul><li>Fluoxetine </li></ul><ul><li>Sertraline </li></ul><ul><li>Fluvoxamine </li></ul><ul><li>Paroxetine </li></ul>Fluoxetine Sertraline
    9. 9. <ul><li>SNRI--- </li></ul><ul><li>Venlafaxine </li></ul><ul><li>Duloxetine </li></ul><ul><li>NaSSA --- </li></ul><ul><li>Mirtazapine </li></ul><ul><li>SARI--- </li></ul><ul><li>Trazodone </li></ul><ul><li>NDRI--- </li></ul><ul><li>Buproprion </li></ul><ul><li>NaRI--- </li></ul><ul><li>Reboxetine </li></ul>
    10. 10. Why selective?? <ul><li>Affect only the reuptake pumps responsible for 5HT </li></ul><ul><li>Because of this, SSRIs lack some of the side effects of the more general drugs </li></ul>
    11. 11. History Of SSRI’s <ul><li>SSRI’s were introduced in 1987 </li></ul><ul><li>The first was Fluoxetine (Prozac:Eli Lilly & Company) FDA approved 1987 </li></ul><ul><li>Sertraline (Zoloft; Pfizer, Inc) FDA approved 1991 </li></ul><ul><li>Paroxetine (Paxil; GlaxoSmithKline) FDA approved 1992 </li></ul><ul><li>Citalopram (Celexa; Forest Pharmaceuticals) FDA approved 2000 </li></ul><ul><li>Escitalopram (Lexapro; Forest Pharmaceuticals) FDA approved 2002 </li></ul>
    12. 12. Serotonin <ul><li>Also known as 5-HT, derived from tryptophan (amino acid) </li></ul><ul><li>It is widely distributed in the animal and vegetable kingdoms </li></ul><ul><li>In mammals it is found in --- </li></ul><ul><li>gastrointestinal enterochromaffin cells </li></ul><ul><li>blood platelets </li></ul><ul><li>Brain </li></ul><ul><li>nerve tissue </li></ul>(McGraw-Hill Encyclopedia of Science and Technology, 2005)
    13. 13. Serotonin (contd.) <ul><li>Serotonin is concentrated in certain areas of the brain--- </li></ul><ul><li>the hypothalamus </li></ul><ul><li>midbrain </li></ul><ul><li>the cortex </li></ul><ul><li>Cerebellum </li></ul>
    14. 16. Other indications of SSRI <ul><li>Anxiety disorders : </li></ul><ul><li>generalized anxiety </li></ul><ul><li>panic disorder </li></ul><ul><li>social phobia </li></ul><ul><li>obsessive-compulsive disorder </li></ul><ul><li>Bulimia nervosa </li></ul><ul><li>Pathological gambling </li></ul>
    15. 17. SNRIs <ul><li>SNRIs were developed more recently than SSRIs </li></ul><ul><li>Relatively few </li></ul><ul><li>Their efficacy as well as their tolerability appears to be somewhat better than the TCA’s. </li></ul>
    16. 18. Venlafaxine <ul><li>venlafaxine is approximately 3- to 5-fold more potent at inhibiting serotonin than noradrenaline reuptake </li></ul><ul><li>It has low affinity for cholinergic, histamine H1 and adrenergic receptors. </li></ul><ul><li>Venlafaxine is the first and most commonly used SNRI. </li></ul>Venlafaxine
    17. 19. Recognized minimum effective doses in MDD <ul><li>SSRIs </li></ul><ul><ul><li>Citalopram 20 mg/day </li></ul></ul><ul><ul><li>Escitalopram 10 mg/day </li></ul></ul><ul><ul><li>Fluoxetine 20 mg/day </li></ul></ul><ul><ul><li>Fluvoxamine 50 mg/day </li></ul></ul><ul><ul><li>Paroxetine 20 mg/day </li></ul></ul><ul><ul><li>Sertraline 50 mg/day </li></ul></ul>
    18. 20. Recognized minimum effective doses – antidepressants (except TCAs) <ul><li>Others </li></ul><ul><ul><li>Duloxetine 60 mg/day </li></ul></ul><ul><ul><li>Mirtazapine 30 mg/day </li></ul></ul><ul><ul><li>Reboxetine 8 mg/day </li></ul></ul><ul><ul><li>Trazodone 150 mg/day </li></ul></ul><ul><ul><li>Venlafaxine 75 mg/day </li></ul></ul>
    19. 21. Licensed Dosing <ul><li>Citalopram--- 20-60mg/day </li></ul><ul><li>Escitalopram--- 10-20mg/day </li></ul><ul><li>Fluoxetine--- 20-60mg/day </li></ul><ul><li>Sertraline--- 50-200mg/day </li></ul><ul><li>Fluvoxamine--- 100-300mg/day </li></ul><ul><li>Paroxetine--- 20-60mg/day </li></ul>
    20. 22. Licensed Dosing <ul><ul><li>Duloxetine 60-120 mg/day </li></ul></ul><ul><ul><li>Mirtazapine 15-45 mg/day </li></ul></ul><ul><ul><li>Reboxetine 8-12 mg/day </li></ul></ul><ul><ul><li>Trazodone 150-300 mg/day </li></ul></ul><ul><ul><li>Venlafaxine 75-375 mg/day </li></ul></ul>
    21. 23. Plasma half life Fluvoxamine Paroxetine Sertraline Fluoxetine Escitalopram Citalopram 17-22h 24h 26h 4-6 days 30h 33h
    22. 24. Adverse Effects (A/Es) of SSRIs <ul><li>Nausea, vomiting, dyspepsia </li></ul><ul><li>Irritability/ agitation </li></ul><ul><li>Insomnia </li></ul><ul><li>Skin rash </li></ul><ul><li>Sexual dysfunction </li></ul><ul><li>Hyponatraemia </li></ul><ul><li>Cutaneous/ GI bleeding </li></ul><ul><li>Discontinuation syndrome </li></ul>
    23. 25. Adverse Effects (A/Es) of SSRIs Nausea+ Fluvoxamine Discontinuation sym++ Paroxetine A/E Sertraline Insomnia++ Agitation++ Rash+ Fluoxetine A/E Escitalopram Agitation, Insomnia Citalopram
    24. 26. Major interactions (CP 450 inhibitor) Fluoxetine Sertraline Fluvoxamine Paroxetine Citalopram Escitalopram Avoid - MAOi, St. John’s wort. Plasma level of some antipsychotics/some benzos/carbamazepine/TCAs plasma level of theophylline (Fluvo) Avoid - MAOi, St. John’s wort. Caution with alcohol, NSAID’s, Warferin
    25. 27. Serotonin syndrome
    26. 28. Features of Serotonin Syndrome <ul><li>Classic clinical triad: </li></ul><ul><ul><li>Mental status changes </li></ul></ul><ul><ul><li>Autonomic hyperactivity </li></ul></ul><ul><ul><li>Neuromuscular abnormalities </li></ul></ul><ul><li>Wide ranging symptoms </li></ul>
    27. 29. Serotonin syndrome (contd.)
    28. 30. Serotonin syndrome (contd.)
    29. 31. Discontinuation Symptoms <ul><li>Paroxetine commonest </li></ul><ul><li>Venlafaxine </li></ul>
    30. 32. Antidepressant-induced hyponatraemia <ul><li>Risk factors </li></ul><ul><li>Old age </li></ul><ul><li>Female sex </li></ul><ul><li>Low body weight </li></ul><ul><li>Low baseline sodium concentration </li></ul><ul><li>Some drug treatments (e.g. diuretics, NSAIDs, carbamazepine, cancer chemotherapy) </li></ul><ul><li>Reduced renal function (especially acute and chronic renal failure) </li></ul><ul><li>Medical co-morbidity (e.g. hypothyroidism, diabetes, COPD, hypertension, head injury, CAD, various cancers) </li></ul><ul><li>Warm weather (summer) </li></ul>
    31. 33. Antidepressant-induced hyponatraemia- monitoring <ul><li>All patients taking antidepressants should be </li></ul><ul><li>observed for signs of hyponatraemia </li></ul><ul><li>( dizziness, nausea, lethargy, confusion, </li></ul><ul><li>cramps, seizures ). </li></ul><ul><li>Serum sodium should be determined (at </li></ul><ul><li>baseline and 2 and 4 weeks, and then 3- </li></ul><ul><li>monthly ) for those at high risk of drug- </li></ul><ul><li>induced hyponatraemia. </li></ul>
    32. 34. Special situations <ul><li>Post stroke depression— </li></ul><ul><li>SSRIs </li></ul><ul><li>Mirtazapine </li></ul><ul><li>30-40% stroke pts develop MDD. </li></ul>
    33. 35. Special situations <ul><li>SSRIs and bleeding---- </li></ul><ul><li>Pts with haemostatic defects </li></ul><ul><li>Pts taking warferin or antiplatelet drugs </li></ul><ul><li>NSAID’s </li></ul><ul><li>Steroids </li></ul><ul><li>P/h/o GI bleeding </li></ul>
    34. 36. Special situations <ul><li>In Diabetes Mellitus --- </li></ul><ul><li>SSRI’s </li></ul><ul><li>SNRI’s </li></ul><ul><li>Mirtazapine </li></ul><ul><li>TCA </li></ul>
    35. 37. Special situations <ul><li>In elder people– </li></ul><ul><li>SSRI’s </li></ul><ul><li>In Post MI patients- </li></ul><ul><li>SSRI’s </li></ul><ul><li>Mirtazapine </li></ul>
    36. 38. Special situations <ul><li>In pregnancy- -- </li></ul><ul><li>Fluoxetine </li></ul><ul><li>TCAs </li></ul><ul><li>In breast feeding mother- -- </li></ul><ul><li>Sertraline </li></ul><ul><li>Paroxetine </li></ul>
    37. 39. Special situations <ul><li>In renal impairment — </li></ul><ul><li>Citalopram </li></ul><ul><li>Sertraline </li></ul><ul><li>In hepatic impairment — </li></ul><ul><li>Citalopram </li></ul><ul><li>Paroxetine </li></ul>
    38. 40. Key points that patients should know <ul><li>A single episode of depression should be treated for at least 6–9 months after remission </li></ul><ul><li>The risk of recurrence of depressive illness is high and increases with each episode </li></ul><ul><li>Those who have had multiple episodes may require treatment for many years .The chances of staying well are greatly increased by taking antidepressants </li></ul>
    39. 41. Key points that patients should know <ul><li>Antidepressants are: </li></ul><ul><ul><ul><li>effective </li></ul></ul></ul><ul><ul><ul><li>not addictive </li></ul></ul></ul><ul><ul><ul><li>not known to lose their efficacy over time </li></ul></ul></ul><ul><ul><ul><li>not known to cause new long-term side effects </li></ul></ul></ul><ul><li>The medication needs to be reduced slowly under the supervision of a doctor </li></ul>
    40. 42. Key points that patients should know <ul><li>Medication needs to be continued at the treatment dose. If side effects are intolerable, it may be possible to find a more suitable alternative </li></ul><ul><li>If patients decide to stop their medication, this must not be done suddenly, as this may lead to unpleasant discontinuation effects </li></ul>
    41. 43. NICE guidelines on the treatment of depression <ul><li>Antidepressants are not recommended as first-line treatment in recent-onset, mild depression </li></ul><ul><li>Antidepressants are recommended for the treatment of moderate to severe depression and for dysthymia </li></ul>
    42. 44. NICE guidelines on the treatment of depression <ul><li>For severe depression , a combination of an antidepressant and CBT is recommended </li></ul><ul><li>For treatment-resistant depression recommended strategies include augmentation with lithium, an antipsychotic or a second antidepressant </li></ul><ul><li>Patients with two prior episodes and functional impairment should be treated for at least 2 years </li></ul><ul><li>The use of ECT is supported in severe and treatment-resistant depression </li></ul>
    43. 45. NICE guidelines on the treatment of depression <ul><li>When an antidepressant is prescribed, a generic SSRI is recommended </li></ul><ul><li>All patients should be informed about the withdrawal (discontinuation) effects of antidepressants </li></ul>
    44. 46. NICE guidelines on the treatment of anxiety disorders with SSRIs <ul><li>½ of the dose used in MDD. </li></ul><ul><li>Response – 6-8 wks </li></ul><ul><li>Duration of treatment-- ?? 6-8 months </li></ul>
    45. 48. Thank you all….
    46. 49. List of people with depression <ul><li>Abraham Lincoln (US president) </li></ul><ul><li>William James & John B. Watson (pioneer psychologists) </li></ul><ul><li>Sir Winston Churchill (British Prime Minister ) </li></ul><ul><li>Brooke Shields (American actress) </li></ul><ul><li>John Denver ( singer) </li></ul>
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